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anti-leukemic activity of FLT3 inhibitor on childhood acute lymphoblastic leukemia with 11q23 translocation

FLT3抑制剂对11q23易位儿童急性淋巴细胞白血病的抗白血病活性

基本信息

批准号：
16591018
负责人：
SUGITA Kanji
金额：
$ 2.18万
依托单位：
University of Yamanashi
依托单位国家：
日本
项目类别：
Grant-in-Aid for Scientific Research (C)
财政年份：
2004
资助国家：
日本
起止时间：
2004 至 2005
项目状态：
已结题

来源：
https://kaken.nii.ac.jp/en/grant/KAKENHI-PROJECT-16591018/
关键词：
PKC412 anti-FLT3 agent 11q23 translocation childhood ALL apoptosis cell cycle arrest 白血病細胞株 STAT5 Bim 小児急性白血病

项目摘要

We examined the anti-leukemic activity of PKC412 (a kinase inhibitor of FLT3) against 11q23-translocated leukemia cell lines with or without D835 mutation and pursued the molecular mechanism(s) of its activity. B-precursor leukemic cell lines with 11q23 translocation expressed a higher FLT3 transcript on the real-time PCR analysis and showed a higher inhibition of ^3H-thymidine uptakes by PKC412 when compared with other B-precursor cell lines. This anti-leukemic activity of PKC412 was more profoundly revealed in 11q23-traslocated cell lines with D835 mutation, and was mainly mediated by the caspase-dependent induction of apoptosis. The PKC412-induced cell cycle arrest at the G0/G1 phase was also revealed in 11q23-translocated cell lines with or without D835 mutation. Regarding changes in signaling molecules after PKC412 treatment, constitutive phosphorylation of STAT5 and Akt was almost completely abolished and the proapoptotic BH3-only member Bim was strikingly upregulated, suggesting their causative roles in the PKC412-induced apoptosis. These results shed light on the molecular mechanism of the anti-leukemic activity of the FLT3 inhibitor(s) and provide a molecular basis to the prospect that PKC412 might become a potentially useful agent for the treatment of leukemia with 11q23 translocation, particularly having FLT3-TKD mutations.

我们检测了FLT 3激酶抑制剂PKC 412对11 q23易位白血病细胞系（有或无D835突变）的抗白血病活性，并探讨了其活性的分子机制。与其他B前体细胞系相比，具有11 q23易位的B前体白血病细胞系在实时PCR分析中表达更高的FLT 3转录本，并且显示出PKC 412对^3H-胸苷摄取的更高抑制。PKC 412的这种抗白血病活性在具有D835突变的11 q23-translocated细胞系中更深刻地揭示，并且主要通过半胱天冬酶依赖的凋亡诱导介导。PKC 412诱导的细胞周期阻滞在G 0/G1期也被揭示在11 q23易位细胞株与无D835突变。关于PKC 412处理后信号分子的变化，STAT 5和Akt的组成性磷酸化几乎完全消失，仅促凋亡BH 3成员Bim显着上调，表明它们在PKC 412诱导的细胞凋亡中发挥了致病作用。这些结果阐明了FLT 3抑制剂抗白血病活性的分子机制，并为PKC 412可能成为治疗伴有11 q23易位的白血病，特别是具有FLT 3-TKD突变的白血病的潜在有用药物的前景提供了分子基础。